Strategies for improving the therapy of head and neck cancer should be investigated intensively in order to reduce the morbidity and mortality rates. Induction of selective apoptosis in cancer cells appears to be an effective approach to cancer therapy. We propose to use agents and combinations of agents that can induce apoptosis in head and neck cancer cells in studies designed to assess their potential for therapy of head and neck cancers. Hypothesis: Combinations of retinoids (4HPR and MX335) and farnesyl transferase inhibitor (e.g. FTI SCH66336) have potential to act additively or synergistically to induce apoptosis pathways and enhance cell death in vitro and in vivo and can be effective in the therapy of head and neck cancers. The objectives are: 1) To identify effective agents or combinations thereof among retinoids and FTI that induce apoptosis in vitro in head and neck cancer cells. 2) To analyzed selected agents for their ability to exert therapeutic effects in an animal model of human HNSCC. 3) To conduct a clinical trial in SCCHN patients using a 4HPR/SCH 66366 combination. To accomplish these objectives we shall pursue the following specific aims: 1) To determine the ability of the synthetic retinoids 4HPR and MX335 and the FTI SCH66336 used as single agents and in combination to inhibit the growth, induce apoptosis, and suppress pro-angiogenic activities in several established HNSCC cell lines and normal oral keratinocytes and explore the mechanisms underpinning possible interactions among these agents. 2) To determine the ability of 4HPR, MX335, SCH66336 and their combinations to inhibit the growth of human HNSCC implanted subcutaneously in athymic nude mice and to investigate the mechanisms of the in vivo activity, especially those related to inhibition of cell growth, induction of apoptosis, and inhibition of angiogenesis. 3) To conduct a Phase Ib randomized translational study of 4HPR in combination with SCH66336 in patients with advanced head and neck cancer. Specifically, to estimate the modulation by 4HPR/SCH66336 combination of biological endpoints across four randomly assigned dose levels and to assess the toxicity profile of the 4HPR/SCH66336 combination across four different dose levels. If the results of the 4HPR/SCH66336 combination are favorable then the understanding the biologic interaction between these two promising agents would be important for selecting an appropriate dose combination for future Phase II trials. Furthermore, those biomarkers that are found to be modulated by the 4HPR/SCH66336 combination could be used as intermediate biomarkers in such studies.